RESUMO
Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor-recipient HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Seleção do Doador/normas , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas/normas , Doadores não Relacionados , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Seleção do Doador/métodos , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/normas , Humanos , Recém-Nascido , Sistema de Registros , Doadores não Relacionados/provisão & distribuiçãoRESUMO
There are >24 million registered adult donors, and the numbers of unrelated donor transplantations are increasing. The optimal strategy for prioritizing among comparably HLA-matched potential donors has not been established. Therefore, the objective of the current analyses was to study the association between donor characteristics (age, sex, parity, cytomegalovirus serostatus, HLA match, and blood group ABO match) and survival after transplantation for hematologic malignancy. The association of donor characteristics with transplantation outcomes was examined using either logistic or Cox regression models, adjusting for patient disease and transplantation characteristics associated with outcomes in 2 independent datasets: 1988 to 2006 (N = 6349; training cohort) and 2007 to 2011 (N = 4690; validation cohort). All donor-recipient pairs had allele-level HLA typing at HLA-A, -B, -C, and -DRB1, which is the current standard for selecting donors. Adjusting for patient disease and transplantation characteristics, survival was better after transplantation of grafts from young donors (aged 18-32 years) who were HLA matched to recipients (P < .001). These findings were validated for transplantations that occurred between 2007 and 2011. For every 10-year increment in donor age, there is a 5.5% increase in the hazard ratio for overall mortality. Increasing HLA disparity was also associated with worsening survival. Donor age and donor-recipient HLA match are important when selecting adult unrelated donors. Other donor characteristics such as sex, parity, and cytomegalovirus serostatus were not associated with survival. The effect of ABO matching on survival is modest and must be studied further before definitive recommendations can be offered.
Assuntos
Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados/estatística & dados numéricos , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 × 10(4) T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3(+)-depleted, CD56(+)-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL(+)IL-15Rα(+) artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104.
Assuntos
Ligante 4-1BB/farmacologia , Neoplasias Gastrointestinais/terapia , Doença Enxerto-Hospedeiro/patologia , Interleucina-15/farmacologia , Células Matadoras Naturais/transplante , Transplante de Células-Tronco de Sangue Periférico/métodos , Neoplasias Cutâneas/terapia , Doença Aguda , Adolescente , Transferência Adotiva , Adulto , Células Cultivadas , Feminino , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia , Teste de Histocompatibilidade , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Depleção Linfocítica , Masculino , Irmãos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Quimeras de Transplante , Transplante Homólogo , Falha de Tratamento , Doadores não RelacionadosRESUMO
We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated.
Assuntos
Cadeias beta de HLA-DP/imunologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Adolescente , Adulto , Criança , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Histocompatibilidade , Humanos , Leucemia/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Transplante Homólogo , Doadores não Relacionados , Adulto JovemRESUMO
Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient donor-recipient HLA matching to ensure engraftment and acceptable rates of GVHD. In this Perspective, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Seleção do Doador/normas , Transplante de Células-Tronco Hematopoéticas/normas , Adulto , Células-Tronco Adultas/transplante , Seleção do Doador/estatística & dados numéricos , Teste de Histocompatibilidade , Humanos , Recém-Nascido , Transplante de Células-Tronco de Sangue Periférico/normas , Doadores de Tecidos , Imunologia de Transplantes , Estados UnidosRESUMO
The importance of human leukocyte antigen (HLA) matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA mismatching in NMD is associated with graft failure rather than GVHD.
Assuntos
Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA/imunologia , Doenças Hematológicas/complicações , Histocompatibilidade/imunologia , Adolescente , Adulto , Doadores de Sangue , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Doenças Hematológicas/terapia , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico , Taxa de Sobrevida , Doadores não Relacionados , Adulto JovemRESUMO
The following commentary was developed by the National Marrow Donor Program Cord Blood Advisory Group and is intended to provide an overview of umbilical cord blood (UCB) processing, summarize the current state of potency assays used to characterize UCB, and define limitations of the assays and future needs of the cord blood banking and transplant community. The UCB banking industry is eager to participate in the development of standardized assays to uniformly characterize cellular therapy products that are manufactured in a variety of ways. This paper describes the desired qualities of these assays and how the industry proposes to co-operate with developers to bring relevant assays to market. To that end, the National Marrow Donor Program (NMDP) Cord Blood Bank Network is available to serve as a resource for UCB testing material, research and development consulting, and product/assay testing in an accredited UCB manufacturing environment.
Assuntos
Bioensaio/métodos , Bioensaio/normas , Sangue Fetal , Bancos de Sangue/normas , Transplante de Células/métodos , Humanos , Reprodutibilidade dos TestesRESUMO
The American continent was the last to be occupied by modern humans, and native populations bear the marks of recent expansions, bottlenecks, natural selection, and population substructure. Here we investigate how this demographic history has shaped genetic variation at the strongly selected HLA loci. In order to disentangle the relative contributions of selection and demography process, we assembled a dataset with genome-wide microsatellites and HLA-A, -B, -C, and -DRB1 typing data for a set of 424 Native American individuals. We find that demographic history explains a sizeable fraction of HLA variation, both within and among populations. A striking feature of HLA variation in the Americas is the existence of alleles which are present in the continent but either absent or very rare elsewhere in the world. We show that this feature is consistent with demographic history (i.e., the combination of changes in population size associated with bottlenecks and subsequent population expansions). However, signatures of selection at HLA loci are still visible, with significant evidence selection at deeper timescales for most loci and populations, as well as population differentiation at HLA loci exceeding that seen at neutral markers.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Demografia , Loci Gênicos , Antígenos HLA/genética , Seleção Genética , Alelos , Variação Genética , Geografia , Haplótipos/genética , Heterozigoto , Homozigoto , Humanos , Repetições de Microssatélites/genética , América do Norte , Tamanho da Amostra , América do SulRESUMO
A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well-documented (≥5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.
Assuntos
Alelos , Genética Populacional , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Frequência do Gene , Haplótipos , HumanosRESUMO
In the human killer cell immunoglobulin-like receptors, KIR2DL2, and KIR2DL3, a triad of amino acids in the D1 domain interact to stabilize protein structure. Substitution of any one of these residues caused significant loss of cell surface expression. Although KIR2DS4 and KIR2DS5, two homologous receptors, differ for this triad, flow cytometry analysis of NK and T cell lines transfected with stimulatory KIR genes KIR2DS4 (allele *001) and KIR2DS5 (allele *002) demonstrated cell surface expression. For KIR2DS5, restoration of the triad sequence increased surface expression. Further studies of the receptor encoded by KIR2DS5*002 showed both mature and immature protein isoforms upon gel electrophoresis coupled with surface biotinylation or deglycosylation. In contrast, the KIR2DS5*001 allelic product was not expressed on the cell surface of either NK or T cells and exhibited only a single immature isoform upon gel electrophoresis. Site-directed mutagenesis demonstrated that absence of the KIR2DS5*001-encoded protein at the cell surface was imparted primarily by two amino acid polymorphisms in the D2 domain. Analysis using molecular dynamics simulations suggested that the substitution of a proline for a serine at residue 111 or the substitution of a serine for a phenylalanine at residue 164 caused destabilization of the domain structure and intracellular retention. A third polymorphism at residue 174 impacted the level of KIR2DS5 surface expression. This is the first description at a stimulatory KIR locus of the impact of specific amino acid variations on receptor maturation and the level of surface expression.
Assuntos
Receptores KIR/química , Substituição de Aminoácidos , Biotinilação , Códon/genética , Glicosilação , Humanos , Ligação de Hidrogênio , Células Jurkat/metabolismo , Células Matadoras Naturais/metabolismo , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação Proteica , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Transporte Proteico , Receptores KIR/metabolismoRESUMO
HLA class I assignments were obtained at single genotype, G-level resolution from 98 855 volunteers for an unrelated donor registry in the United States. In spite of the diverse ancestry of the volunteers, over 99% of the assignments at each locus are common. Within this population, 52 novel alleles differing in exons 2 and 3 are identified and characterized. Previously reported alleles with incomplete sequences in the IPD-IMGT/HLA database (n = 519) were selected for full gene sequencing and, from this sampling, another 27 novel alleles are described.
Assuntos
Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade/métodos , Sistema de Registros/estatística & dados numéricos , Análise de Sequência de DNA/métodos , Alelos , Genótipo , Voluntários Saudáveis , Humanos , Estados UnidosAssuntos
Seleção do Doador/normas , Antígenos HLA-B/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade/imunologia , Modelos Moleculares , Alelos , Antígenos/imunologia , Seleção do Doador/métodos , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA-B/química , Antígenos HLA-B/genética , Humanos , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
This report presents serologic equivalents of human leukocyte antigen (HLA)-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, and -DQB1 alleles. The dictionary is an update of the one published in 2001. The data summarize equivalents obtained by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program, recent publications, and individual laboratories. This latest update of the dictionary is enhanced by the inclusion of results from studies performed during the 13th International Histocompatibility Workshop and from neural network analyses. A summary of the data as recommended serologic equivalents is presented as expert assigned types. The tables include remarks for alleles, which are or may be expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated hematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA-based methods. The serological-DNA equivalent dictionary will also aid in typing and matching procedures for organ transplant programs whose waiting lists of potential donors and recipients are comprised of mixtures of serologic and DNA-based typings. The tables with HLA equivalents and a questionnaire for submission of serologic reaction patterns for poorly identified allelic products will be made available through the World Marrow Donor Association Web page (www.worldmarrow.org).
Assuntos
Alelos , Antígenos HLA/classificação , Terminologia como Assunto , Antígenos HLA-A , Antígenos HLA-B , Antígenos HLA-C , Antígenos HLA-DQ , Cadeias beta de HLA-DQ , Antígenos HLA-DR , Cadeias HLA-DRB1 , HumanosAssuntos
Seleção do Doador/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Programas Nacionais de Saúde , Seleção do Doador/normas , Teste de Histocompatibilidade/normas , História do Século XX , História do Século XXI , Humanos , Programas Nacionais de Saúde/história , Programas Nacionais de Saúde/organização & administração , Programas Nacionais de Saúde/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Sistema de Registros , Transplante Homólogo , Estados UnidosRESUMO
The optimal donor of hematopoietic progenitor cells shares alleles of the major histocompatibility genes with the recipient. This chapter describes the strategies aimed at identifying such a matched donor from registries of volunteers or from umbilical cord blood banks.
Assuntos
Antígenos HLA/genética , Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Sistema de Registros , Obtenção de Tecidos e Órgãos/métodos , Alelos , Bancos de Sangue , Sangue Fetal , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Doadores não Relacionados , VoluntáriosRESUMO
DNA sequencing is a powerful technique for identifying allelic variation within the natural killer cell immunoglobulin-like receptor genes. Because of the relatively large size of the KIR genes, each locus is amplified in two or more overlapping segments. Sanger sequencing of each gene from a preparation containing one or two alleles yields a sequence that is used to identify the alleles by comparison with a reference database.
Assuntos
Receptores KIR/genética , Análise de Sequência de DNA , Humanos , FenótipoRESUMO
PURPOSE: Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined. PATIENTS AND METHODS: We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1. RESULTS: Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD. CONCLUSION: In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible.
Assuntos
Transplante de Medula Óssea/métodos , Antígenos de Histocompatibilidade Classe I/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Masculino , Pessoa de Meia-Idade , Irmãos , Doadores de Tecidos , Resultado do TratamentoRESUMO
Genetic polymorphism of KIR2DL4 results in alleles with either 9 or 10 consecutive adenines in exon 6, which encodes the transmembrane domain. "10A" alleles encode a membrane-expressed receptor that is constitutively expressed on resting CD56bright NK cells and on CD56dim cells after culture. However, in some individuals with the 10A allele, KIR2DL4 cannot be detected on their resting CD56bright NK cells. "9A" alleles have been predicted to encode a secreted receptor due to the splicing out of the transmembrane region. In this publication, we show that those individuals with a 10A allele who lack detectable KIR2DL4 on CD56bright NK cells express a KIR2DL4 receptor in which the D0-domain is excised. This Delta-D0 receptor cannot be detected by the available anti-KIR2DL4 monoclonal antibodies. In such individuals, KIR2DL4 becomes detectable on cultured NK cells due to up-regulation of the full-length KIR2DL4 transcript. In all individuals with 10A alleles, KIR2DL4 ceases to be expressed at the cell surface 16 days after activation, despite the maintenance of maximal levels of KIR2DL4 mRNA transcription, suggesting the existence of a negative regulator of cell surface expression. Finally, we show that the 9A allele can produce a secreted KIR2DL4 receptor.